New Insights into Hyperglycemia-induced Molecular Changes in Microvascular Cells

Abstract

Hyperglycemia is the most prevalent characteristic of diabetes and plays a central role in mediating adverse effects on vascular cells during the progression of diabetic vascular complications. In diabetic microangiopathy, hyperglycemia induces biochemical and molecular changes in microvascular cells that ultimately progress to retinal, renal, and neural complications and extends to other complications, including advanced periodontal disease. In this review, we describe changes involving basement membrane thickening, tissue remodeling, gap junctions, inflammation, cytokines, and transcription factors, and their effects on the pathogenesis of diabetic microvascular complications. The majority of the changes described relate to retinal microangiopathy, since ultrastructural, structural, and biochemical alterations have been well-characterized in this tissue.

Immunological Risk Factors for the Development and Progression of Diabetic Retinopathy

“…On one hand it is known that persistent hyperglycaemia leading to the elevation of HbA1c levels may lead to the production and accumulation of advanced glycation end products. Formation of AGEs promotes production of pro-inflammatory cytokines which may further initiate increase of VEGF levels and thus indirectly lead to the development of hypertension in T1DM (Gallego et al, 2008;Roy et al, 2010). It was shown that VEGF binds to VEGFR-2 receptor at the endothelial cell surface which leads to phosphorylation of transcription factors via MAPK (mitogen activated protein kinase) (Suzuma et al, 2001;Wirostko et al, 2008).…”

“…As a result of enhanced vascular permeability, oedemas and haemorrhages appear in the retina. Moreover, the closure of retinal vessels leads to areas with loss of blood flow within retina, which causes its chronic ischaemia and hypoxia and subsequent increase in the production of growth factors that, in turn, induce angiogenesis, formation of arterio-venous anastomoses and proliferation of fibrous tissue within retina and optic nerve disc (Yoshida et al, 2004;Curtis et al, 2009;Roy et al, 2010;Lange et al 2011). It is commonly accepted that hyperglycaemia plays crucial role in pathogenesis of diabetic angiopathy (Roy et al, 2010;Kowluru et al, 2010).…”

“…Moreover, the closure of retinal vessels leads to areas with loss of blood flow within retina, which causes its chronic ischaemia and hypoxia and subsequent increase in the production of growth factors that, in turn, induce angiogenesis, formation of arterio-venous anastomoses and proliferation of fibrous tissue within retina and optic nerve disc (Yoshida et al, 2004;Curtis et al, 2009;Roy et al, 2010;Lange et al 2011). It is commonly accepted that hyperglycaemia plays crucial role in pathogenesis of diabetic angiopathy (Roy et al, 2010;Kowluru et al, 2010). Hyperglycaemia leads to the formation of advanced glycation end products (AGEs) which are durable, irreversible and their characteristic feature is to create cross-links between proteins which in turn affects flexibility of vessels (Wa et al, 2007;Roy et al, 2010;Yamagishi et al, 2011).…”

“…It is commonly accepted that hyperglycaemia plays crucial role in pathogenesis of diabetic angiopathy (Roy et al, 2010;Kowluru et al, 2010). Hyperglycaemia leads to the formation of advanced glycation end products (AGEs) which are durable, irreversible and their characteristic feature is to create cross-links between proteins which in turn affects flexibility of vessels (Wa et al, 2007;Roy et al, 2010;Yamagishi et al, 2011). It was proved that AGEs interaction with receptor for advanced glycation end products (RAGEs) plays a key role in development and progression of late diabetic complications (Thomas et al, 2011;Yamagishi et al, 2011;Zong et al, 2011).…”

Genetics of Endothelial Damage Associated to Diabetes Mellitus Type 2

“…In both DM1 and DM2 the most common macrovascular complications are cardiovascular disease (CVD), cerebral vascular and peripheral vascular disease. In diabetic microangiopathy, hyperglycemia induces biochemical and molecular changes in microvascular cells that ultimately progress to retinal, renal and neural complications and extends to other complications, including advanced periodontal disease (Roy et al, 2010). It is known that already from initial stages (glucose intolerance) the patient is under an important risk of chronic complications, mainly macrovascular coronary damage and also microvascular complications, where retinopathies, neuropathies and diabetic nephropathy (DN) are the most frequent and devastating.…”